The specific aims are to determine the mechanisms of action of genes that induce autoimmunity, lymphoproliferation (1pr), generatlized lymphoproliferative disease (gld), and the Y chromosome of recombinant inbred strain BXSB, and the cellular mechanisms involved in the associated lymphoproliferations. The genes have been transferred to a series of standard inbred strains for the purposes of these studies. The methodologies of genetics, gene transfer by selective breeding and linkage studies, will continue to be applied. The analytic methods of immunogenetics will be applied to gene-gene interactions involving H-2 and I-region genes, nude (nu), hairless (hr), and beige (bg). The immunobiological techniques of bone marrow transplantation will be applied to stem studies of abnormal vs. +/+ marrow cells. The syndromes will be characterized by methods for cenn-mediated immunity, mixed lymphocyte reaction, graft vs. host reaction, natural killer cell activity, and plaque forming ability. Lymphocyte differentiation markers will be quantified by use of a fluorescent activated cell sorter. Enzyme-linked immunosorbent assays will be applied to the quantification of autoantibodies directed against nucleic acid components and to the measurement of rheumatoid factor. The long-term objectives are to establish basic genetic and cellular mechanisms in spontaneous autoimmunity that the applicable to human autoimmune diseases such as Systemic Lupus Erythematosus, Sjogren's syndrome, and rheumatoid arthritis. The elucidation of such mechanisms will permit a rational approach to therapy and will make possible the early recognition of individuals at high rish and the application of rational preventive measures.